Use of L-carnitine for the treatment of cardiovascular diseases

ABSTRACT

The use of L-carnitine, or one of its pharmaceutically acceptable salts, is described in combination with glucose for the preparation of a medicament useful for diminishing the number of deaths caused by acute myocardial infarction, for reducing the number of days infarction patients spend in intensive care in hospital, and for reducing the number of episodes of post-infarction heart failure, in which the L-carnitine is administered intravenously within only a few hours of the onset of symptoms of acute myocardial infarction at an initial dose of 9 grams a day in combination with 1000-1500 mL of a 5% glucose solution for 5 days, after which the L-carnitine treatment is continued at a dose of 4 grams a day administered orally.

This application is a continuation of U.S. application Ser. No.11/629,202 filed on Jan. 8, 2007 which is a 371 U.S. national phase ofInternational Application No. PCT/EP05/06657 filed on Jun. 21, 2005,which claims priority to and benefit of Italian Application No.RM2004A000346 filed on Jul. 13, 2004, all of which are incorporated byreference herein in their entirety.

The present invention relates to the combined use of L-carnitine andglucose as a medicament useful for diminishing the number of deathscaused by acute myocardial infarction, for reducing the number of daysinfarction patients spend in intensive care in hospital, and forreducing the number of episodes of post-infarction heart failure.

The daily dose of L-carnitine to be administered must be dissolved intwo or three 500 ml vials of 5% glucose solution and administeredintravenously. It is important that the treatment with the combinationaccording to the invention should begin within only a few hours of theonset of acute myocardial infarction symptoms, at an initial dose of 9grams a day for 5 days, after which the treatment should be continued ata dose of 4 grams a day with L-carnitine alone, administered orally.

Post-infarction heart failure is due to inability of the heart to pumpblood in sufficient amounts to meet the metabolic needs of the varioustissues.

Acute myocardial infarction (AMI) causes morphofunctional alterationswhich often induce progressive left ventricular dilatation (“ventricularremodelling” phenomenon).

Post-AMI ventricular dilatation may be regarded as a global compensationmechanism aimed at maintaining an adequate cardiac output in thepresence of a reduction in ejection fraction.

The extent of the ventricular dilatation is the most importantprognostic indicator in patients with AMI.

Patients with relatively larger ventricular volumes are at greater riskof future cardiac events (Circulation 1987; 76:44-51).

Limitation of the post-infarction ventricular remodelling phenomenon istherefore of major importance from the clinico-prognostic point of view(Circulation 1994; 89:68-75). Limitation of this phenomenon can beachieved by two mechanisms: (a) by limiting the extent of the infarctedarea (which is the main determinant of future dilatation) by means ofearly myocardial reperfusion (Circulation 1989; 79:441-444) and/or (b)by reducing the parietal stress and consequently the progressivedilatation of the area of the myocardium not involved in the infarctionprocess by means of the administration of ACE inhibitors.

When the thrombotic obstruction evolves rapidly in the direction oftotal, permanent vascular occlusion, the resulting lack of perfusiongives rise, in the space of only a few hours, to myocardial cellularnecrosis and thus to infarction. The immediate and longer-term prognosiswill depend on a series of factors, the most important of which beingthe size of the necrotic area and the early and late complicationsresulting from it. It is therefore obvious that the primary aim ofmodern acute infarction therapy is to reduce the size of the infarctedarea. This aim is often achieved by means of reperfusion procedures,whether pharmacological (thrombolytic), mechanical (PTCA) such asangioplasty, or surgical (by-pass). Generally speaking, the earlier andmore effective the reperfusion, the smaller will be the necrotic area.The latter is also influenced, albeit to a lesser extent, by otherfactors, the first of which is myocardial oxygen consumption, which isconditioned by heart rate, myocardial contractility and parietaltension. Of fundamental importance then will be all those measures,whether pharmacological or otherwise, that reduce the cardiac workload,while at the same time maintaining adequate circulatory output.

Of all subjects who die as a result of acute myocardial infarction, morethan half do so within the first few hours.

Drugs useful for the treatment of heart failure and acute myocardialinfarction are already known.

Beta-blockers are drugs endowed with antiarrhythmia properties and aresignificantly more active if used in the early phases of onset ofinfarction.

Nitroderivatives are drugs usually administered by venous infusion, andare useful for improving myocardial perfusion through vasodilatation ofthe epicardial vessels.

Sodium nitroprusside is a drug that exerts a dual action on thearteriolar and venous districts. This compound produces coronary andrenal vasodilatation, thus enhancing myocardial perfusion and diuresis.

L-carnitine is a known compound, whose preparation process is describedin U.S. Pat. No. 4,254,053.

The use of L-carnitine in combination with glucose is already known.

U.S. Pat. No. 4,320,145 describes a glucose solution containingL-carnitine which is useful for favouring the muscular absorption of theglucose and thus for preventing excessive insulin secretion.

The use of L-carnitine for the treatment of heart diseases is alsoknown.

In Drugs Exp. Clin. Res 1992; 18(8):355-65 the use of L-carnitine isdescribed in infarction patients, in whom oral treatment withL-carnitine was initiated after the patients had been discharged fromhospital.

In Eur Heart J. 1989 June; 10(6):502-8 the use of L-carnitine isdescribed in infarction patients, in whom the antiarrhythmia andmetabolic effects of L-carnitine are evaluated. In this study, it isreported that there were two deaths each in the group treated withL-carnitine and in that treated with placebo.

In J. Am. Coll. Cardiol 1995 August; 26(2):380-7 the prolonged use ofL-carnitine in infarction patients is described, and its effect on leftventricular volume at 3, 6 and 12 months after the start of treatment.In this study, L-carnitine was administered within 24 hours of theinfarction and the mortality assessment showed that 11 patients in thetreated group died over the entire hospitalisation period as against 14in the control group. The non-significance of the difference in thenumber of deaths observed in the two groups tested is evident.

In Am. Heart J. 2000 February; 139(2 Pt 3):S115-9, which is a review ofthe metabolic effects of L-carnitine in the cardiological field, it isreported that L-carnitine is effective because it has metabolic effectson lipid and carbohydrate metabolism.

In Lancet 1982 Jun. 19; 1(8286):1419-20 it is reported that analyses ofheart tissue samples of patients dying of infarction, in parallel withheart tissue samples from people dying due to causes other than infarct,show that in the cardiac areas not affected by infarction (ofcardiopathic patients) the level of free carnitine was equal to that ofcontrols, whereas the level of free carnitine in the area of infarctedheart tissue was lower than that in controls.

In Postgrad Med. J. 1996 January; 72(843):45-50 the use of L-carnitineis described in patients presenting infarction symptoms in the 24-hourperiod prior to the start of treatment. In this study, L-carnitine wasadministered at a dose of 2 g/day, and the number of deaths at 28 daysafter the start of treatment was 6 in the control group and 4 in thetreated group. The non-significance of the difference in the number ofdeaths observed in the two groups tested is evident.

In Am. J. Cardiovasc Pathol 1990; 3(2):131-42 the use of L-carnitine isdescribed in an experimental cardiac ischaemia model in experimentalanimals (dogs) where L-carnitine proved active in enhancing cardiaclipid metabolism in these animals.

In Drugs Exptl. Clin. Res. X(4) 219-223 (1984) the use of L-carnitine ata dose of 40 mg/kg/day (2.8 g/day) is described. The number of deaths inthe control group was one, as against none in the treated group.Moreover, in this study the treated group was divided into two subgroupsone of which was treated with L-carnitine within 4 hours of onset ofsigns of infarction and the other treated 4 hours after the onset ofsigns of infarction. In their discussion of the results the authorsstate that they found no statistically significant difference betweenpatients treated within 4 hours of onset of symptoms of infarction andpatients treated 4 hours after the onset of such symptoms.

In a further publication entitled “Clinical aspects of human carnitinedeficiency” published by “Pergamon Press 1986” a “blind” clinical trialis described in which 351 patients with acute myocardial infarction wererecruited whose infarction symptoms had set in within 8 hours of thestart of treatment with L-carnitine. In this clinical trial the patientsreceived 3 grams of L-carnitine every 8 hours (9 grams a day)intravenously. The L-carnitine treatment was continued for 48 hours (thecontrol group received saline solution). Analysis of the mortality at 7days after the start of treatment showed no significant differencebetween the control groups and the group treated with L-carnitine.

In none of these studies with L-carnitine (or other studies notmentioned in the present application) is it claimed or suggested thatL-carnitine in combination with glucose is useful for the treatment ofpost-infarction heart failure, for reducing the number of daysinfarction patients spend in intensive care in hospital, and forreducing the number of deaths caused by acute myocardial infarction.

A certain number of patients with acute myocardial infarction stillcontinue to die during the first week of hospitalisation in intensivecare departments, and also later, even when treated with all theappropriate pharmacological and technical means available. Furthermore,L-carnitine alone, whether using the therapeutic regimens adopted todate and described in the above-cited publications, or in combinationwith said appropriate and available pharmacological and technical means,though improving the general condition of the patients treated, fails toreduce the mortality compared to patients treated with the normal drugsused.

There is therefore still a strongly perceived need for new drugs or newcombinations useful for diminishing the number of deaths caused by acutemyocardial infarction, for reducing the number of days infarctionpatients spend in intensive care in hospital, and for reducing thenumber of episodes of post-infarction heart failure.

It has now surprisingly and unexpectedly been found that the combineduse of L-carnitine or one of its pharmaceutically acceptable saltstogether with glucose is useful for diminishing the number of deathscaused by acute myocardial infarction, for reducing the number of daysinfarction patients spend in intensive care in hospital, and forreducing the number of episodes of post-infarction heart failure.

What is meant by the combined use of L-carnitine and glucose is thesimultaneous administration of a 5% glucose solution (1000/1500 mL/dayi.v.) in which 9 grams of L-carnitine are dissolved, or theadministration of 5% glucose solution (1000/1500 mL/day i.v.) and theparallel administration of 9 grams/day i.v. of L-carnitine in a singledose or in divided doses (e.g. 3 g×3 administrations/day i.v).

What is meant by pharmaceutically acceptable salt of L-carnitine is anysalt of the latter with an acid that gives rise to no toxic or sideeffects.

These acids are well known to pharmacologists and to experts inpharmacy; non-limiting examples of such salts are: chloride, bromide,orotate, aspartate, acid aspartate, acid citrate, magnesium citrate,phosphate, acid phosphate, fumarate and acid fumarate, magnesiumfumarate, lactate, maleate and acid maleate, oxalate, acid oxalate,pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate,tartrate and acid tartrate, glycerophosphate, mucate, magnesiumtartrate, 2-amino ethanesulphonate, magnesium 2-amino ethanesulphonate,methanesulphonate, choline tartrate, trichloroacetate, andtrifluoroacetate.

What is meant by pharmaceutically acceptable salt of L-carnitine is alsoa salt approved by the FDA and listed in the publication Int. J. ofPharm. 33 (1986), 201-217, incorporated herein as a reference.

The object of the present invention then is the combined use ofL-carnitine or one of its pharmaceutically acceptable salts incombination with glucose, in which the intravenous treatment withL-carnitine and glucose is initiated within only a few hours of onset ofthe symptoms of acute myocardial infarction, preferably within 6 hours,and more preferably within 4 hours of the onset of acute myocardialinfarction symptoms; the treatment is administered for 5 daysconsecutively at an initial L-carnitine dose of 9 grams a day dissolvedin 1000-1500 mL of 5% glucose solution, after which the L-carnitinetreatment is continued orally at a dose of 4 grams a day; for thepreparation of a medicament useful for diminishing the number of deathscaused by acute myocardial infarction, for reducing the number of daysinfarction patients spend in intensive care in hospital, and forreducing the number of episodes of post-infarction heart failure.

The following example illustrates the invention.

EXAMPLE 1

A clinical trial was conducted aimed at evaluating the effect of theadministration of L-carnitine on short-, medium- and long-term incidenceand mortality in patients with acute myocardial infarction. The trialdesign was that of a multicentre randomized, double-blind,placebo-controlled, parallel-group trial.

A total of 2,296 patients of male and female sex were recruited, agedbelow 80 years, subdivided into groups. The study compound, L-carnitine,was administered at a dose of 9 g/day i.v. for the first 5 days and 4g/day by mouth from day 6 to day 180.

In particular, in one group of patients the L-carnitine was administeredintravenously dissolved in sterile saline solution, while in anothergroup of patients it was administered dissolved in normal 5% glucosesolution used in hospital departments.

The control group received the standard therapy used for the treatmentof infarct, without L-carnitine.

Concomitant therapies were administered according to the proceduresadopted in local clinical practice.

The efficacy parameters evaluated were reduction of mortality, reductionof the number of days spent in intensive care, and reduction of thenumber of episodes of post-infarction heart failure.

Inclusion Criteria

-   -   Typical chest pain lasting >30 minutes which is not relieved by        oral or i.v. administration of nitrates;    -   ECG with ST-segment elevation 0.2 mV in D, and in lead aVL        and/or in at least two contiguous precordial leads;    -   Time interval elapsing between onset of symptoms and study        randomisation <12 hours;    -   Age <80 years;    -   Written informed consent.        Exclusion Criteria    -   Pregnancy or breast-feeding;    -   Haemodynamically significant valvulopathy;    -   Hypertrophic or dilatory cardiomyopathy;    -   Congenital cardiopathy;    -   Clinically severe liver and kidney disease;    -   Alcohol abuse;    -   Other diseases associated with a poor life expectancy;    -   Conditions making poor compliance with treatment and/or periodic        examinations likely;    -   Inclusion in another trial.

The patients treated with 9 g/day of L-carnitine dissolved in 1000/1500mL of glucose solution showed a lower mortality rate than the controlgroup, and said mortality was comparable to that recorded in the grouptreated with L-carnitine dissolved in saline. For this reason, Table 1/Ahere below gives the mortality data in the placebo group compared topatients treated with L-carnitine, regardless of whether the L-carnitinewas dissolved in saline or in glucose solution (totality of patientsincluded in the trial).

TABLE 1/A NUMBER OF DEATHS AT: 3 5 7 days days days 1 mo. 2 mos. 6 mos.12 mos. Placebo 34 43 45 58 65 74 75 L-carnitine 23 27 31 45 53 64 67 RR0.68 0.63 0.69 0.78 0.81 0.86 0.89 P 0.1357 0.0498 0.097 0.1766 0.2380.3546 0.4555 RR = Relative Risk.

Table 1/B here below gives the mortality data in the patient grouptreated with L-carnitine dissolved in glucose solution compared to thecontrol group treated with placebo.

TABLE 1/B NUMBER OF DEATHS AT: 3 5 7 days days days 1 mo. 2 mos. 6 mos.12 mos. Placebo 17 21 22 29 33 37 38 L-carnitine 11 13 15 22 26 32 33 RR0.67 0.64 0.70 0.79 0.80 0.87 0.88 P 0.1356 0.0497 0.099 0.1768 0.2370.3548 0.4553 RR = Relative Risk.

The group of infarction patients treated with L-carnitine dissolved inglucose solution presented a statistically significant reduction in thenumber of days in intensive care compared to the group of patientstreated with L-carnitine dissolved in saline. The results obtained arereported in Table 2.

TABLE 2 LENGTH OF STAY IN INTENSIVE CARE UNIT L-carnitine in saline 6days L-carnitine and glucose 5 days solution Significance P ≦ 0.05

The group of patients treated with L-carnitine and glucose solutionshowed a statistically significant reduction in the number of episodesof post-infarction heart failure compared to the patient group treatedwith L-carnitine dissolved in saline.

The results obtained are reported in Table 3.

TABLE 3 EPISODES OF POST-INFARCTION HEART FAILURE L-carnitine in salinen = 16 L-carnitine and glucose n = 9 solution Significance P ≦ 0.001

The L-carnitine doses used according to the present invention and thetreatment regimen may be subject to changes, as advised by the primarycare physician on the basis of his or her experience and the patient'sgeneral condition, also thanks to the lack of toxicity of the compoundaccording to the invention.

The intravenous administration formulations, according to the presentinvention, include solutions or suspensions in suitable vehicles suchas, for example, saline solution, distilled water, glucose solution, orothers.

The oral administration formulations, according to the presentinvention, include tablets, capsules, powders, granules, syrups,elixirs, solutions or suspensions.

1. A method for reducing the number of episodes of death caused by acutemyocardial infarction in patients as compared to a control group treatedwith L-carnitine in saline comprising intravenously administeringL-carnitine or one of its pharmaceutically acceptable salts within 6hours of the onset of symptoms of acute myocardial infarction topatients in need thereof, at an initial dose of 9 grams a day, incombination with 1000-1500 ml of a 5% glucose solution for 5 days,followed by orally administering the L-carnitine or one of itspharmaceutically acceptable salts at a dose of 4 grams a day, wherebysaid number of episodes of death caused by acute myocardial infarctionare reduced compared to said control group.
 2. The method according toclaim 1, in which the L-carnitine and the glucose solution areadministered within 4 hours of the onset of symptoms of acute myocardialinfarction.
 3. The method according to claim 1, in which thepharmaceutically acceptable salt of L-carnitine is selected from thegroup consisting of chloride, bromide, orotate, aspartate, acidaspartate, acid citrate, magnesium citrate, phosphate, acid phosphate,fumarate and acid fumarate, magnesium fumarate, lactate, maleate andacid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulphate,acid sulphate, glucose phosphate, tartrate and acid tartrate,glycerolphosphate, mucate, magnesium tartrate, 2-amino ethanesulphonate,magnesium 2-amino ethanesulphonate, methanesulphonate, choline tartrate,trichloroacetate, and trifluoroacetate.
 4. The method according to claim1, in which the L-carnitine is administered dissolved in 1000-1500 mL of5% glucose solution.
 5. The method according to claim 1, in which theL-carnitine is administered in parallel to the glucose solution, in asingle dose or in divided doses, dissolved in a suitable vehicle suchas, for example, distilled water, saline solution, or glucose solution.6. The method according to claim 1, in which the L-carnitine for oraladministration is in the form of tablets, capsules, powders, granules,syrups, elixirs, suspensions or solution.